The principal objective of this research is to learn how well-differentiated cells such as myocardial cells react to lethal and non-lethal injury, especially lethal and non-lethal ischemic injury. Our specific aim is to determine the event or series of events occurring within ischemic myocardial cells which dictate that the injury is irreversible, i.e, that the cells have passed the "point-of-no-return." Also proposed are studies of the structural and functional changes occurring during the phase of reversible injury with the aim of determining means of preventing or modifying the cell's response to injury. Specific studies on the causes of mitochondrial dysfunction in cells which just have entered a state of irreversible ischemic injury are planned as are experiments aimed at learning the pathogenesis of the amorphous intramitochondrial densities which we have shown to be characteristic of irreversible ischemic injury in heart and kidney tissue. In vivo and in vitro assessment of cell membrane function in reversible and irreversible injury are proposed. Lastly, studies of the zonal distribution of areas of cell death in acute experimental myocardial infarcts in the dog heart are planned as are experiments designed to determine the effects of agents which may prevent or reverse the onset of ischemic cell death in vivo.